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Periodontol 2000. Author manuscript; available in PMC 2023 June 01.
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Published in final edited form as:

Periodontol 2000. 2022 June ; 89(1): 9–18. doi:10.1111/prd.12430.

Interconnection of periodontal disease and comorbidities:

evidence, mechanisms, and implications
George Hajishengallis
Department of Basic and Translational Sciences, Penn Dental Medicine, University of
Pennsylvania, Philadelphia, PA, USA

Abstract
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Periodontitis, a microbiome-driven inflammatory disease of the tooth-attachment apparatus,

is epidemiologically linked with other disorders, including cardio-metabolic, cognitive
neurodegenerative and autoimmune diseases, respiratory infections, and certain cancers. These
associations may, in part, be causal, as suggested by interventional studies showing that local
treatment of periodontitis reduces systemic inflammation and surrogate markers of comorbid
diseases. The potential cause-and-effect connection between periodontitis and comorbidities is
corroborated by studies in preclinical models of disease, which additionally provided mechanistic
insights into these associations. This overview discusses recent advances in our understanding
of the periodontitis-systemic disease connection, which may potentially lead to innovative
therapeutic options to reduce the risk of periodontitis-linked comorbidities.
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1. Introduction
Periodontitis is an exemplar of a microbe-driven chronic inflammatory disease that persists
in susceptible individuals, in part due to reciprocally reinforced interactions between
the dysbiotic microbiome and the host inflammatory response 1,2. In its severe form,
periodontitis is the sixth most prevalent condition in the world and afflicts about 10% of
the adult population 3,4. If untreated, periodontitis leads to progressive destruction of the
tooth-attachment apparatus (gingiva, cementum, periodontal ligament and alveolar bone)
and eventual tooth loss, while compromising mastication and esthetics and affecting the
quality of life 5–9. Standard-of-care therapy (scaling and root planing often with adjunctive
anti-microbial approaches) is not always effective, especially in highly susceptible patients,
and thus periodontitis poses as a serious public health and socioeconomic problem 7,10–12.
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The combined direct and indirect costs (due to loss in productivity) of periodontal disease in
the USA and Europe were estimated, respectively, at $154.06 billion and €158.64 billion 13.

Periodontitis is moreover linked epidemiologically with other disorders, including

cardiovascular disease, type-2 diabetes, obesity, rheumatoid arthritis, osteoporosis,
respiratory infections, inflammatory bowel disease, Alzheimer’s disease, nonalcoholic
fatty liver disease, chronic kidney disease and certain cancers 14–18 (Figure 1). From a

*
Correspondence: geoh@upenn.edu, George Hajishengallis, D.D.S., Ph.D., Thomas W. Evans Centennial Professor, Penn Dental
Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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medical and therapeutic perspective, it is essential to understand whether the association

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of periodontitis with comorbid disorders is simply of correlative nature or whether arises

also from causal interactions. In the latter regard, a possible mechanism contributing to
the independent association of periodontitis and inflammatory comorbidities may involve
periodontitis-associated low-grade systemic inflammation, which is a common denominator
of many chronic conditions 14,19. Conversely, systemic diseases also affect periodontitis,
for instance type-2 diabetes may aggravate periodontitis, in part, by augmenting the
inflammatory burden on the periodontal tissues and by adversely affecting the composition
of the periodontal microbiome 14,20,21.

Periodontitis-associated systemic inflammation is thought to arise from hematogenous

translocation of periodontal microorganisms or the spillover of inflammatory cytokines and
other mediators from the periodontium to the circulation 17,22 (Figure 2). Although the
oral microbiome does not comprise solely bacteria, the association of periodontitis with
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systemic disease has been primarily investigated in the context of the bacteriome, despite
emerging evidence that viruses (and other types of microorganisms) may influence the host
periodontal response as well as synergize with periodontal bacterial pathogens 23–26. It has
also been suggested that locally activated lymphocytes (from the draining lymph nodes of
the periodontium) may disseminate via the lymphatic circulation to extraoral tissues, where
they could exacerbate tissue inflammation 27 (Figure 2). Periodontitis-associated systemic
inflammation could additionally contribute to maladaptive rewiring of hematopoietic
progenitors in the bone marrow, giving rise to increased production of mature myeloid cells
with increased inflammatory responsiveness (a process known as ‘trained myelopoiesis’),
hence potentially affecting multiple comorbidities 19,28 (Figure 2). Disseminated periodontal
microbes may also have direct pathogenic effects in extra-oral tissues, thus becoming
involved in lung infections, endothelial dysfunction, gut dysbiosis, and cancer-promoting
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functions 27,29–33. In the latter regard, certain types of cancer (e.g., colorectal cancer and
oral/orodigestive squamous cell carcinoma) are increasingly appreciated as a comorbidity
associated with specific periodontal pathogens.

These mechanistic insights, mostly derived from studies in preclinical models, imply that
periodontitis is a modifiable risk factor for comorbidities, a notion that is supported by
clinical interventional studies, which showed that treatment of periodontitis attenuates
systemic inflammation and surrogate markers of comorbidities 34–36. Accordingly, emerging
adjunctive host-modulation therapies, (e.g., complement-targeted intervention with efficacy
in phase 2a trial in patients with periodontal inflammation 37,38), to improve periodontal
treatment (beyond the level achieved by conventional approaches alone) acquire increased
importance, as they could help reduce the risk of systemic comorbidities 39,40.
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In this volume, clinical and basic scientists, with expertise in the pathogenesis of
periodontitis and associated disorders, review in detail the association of periodontitis with
extra-oral comorbidities and its implications for the overall health.

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2. Cardiometabolic disorders and endotoxemia

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Periodontitis is bidirectionally associated with cardiometabolic disorders. The translocation

of bacterial lipopolysaccharide (LPS) into the blood circulation causes endotoxemia,
which is associated with increased risk of cardiometabolic disorders. Although the major
source of endotoxemia is thought to be the intestinal microbiota, the dysbiotic periodontal
microbiota may also contribute to endotoxemia in patients with periodontitis, as discussed
by Pussinen et al 41. The authors review the basic biology of LPS and its host receptor
complex (Toll-like receptor 4 and co-receptors) as well as the concept of endotoxemia as a
plausible molecular mediator between periodontitis and the elevated risk of cardiometabolic
conditions. These include cardiovascular disease, obesity, insulin resistance, type 2 diabetes,
non-alcoholic fatty liver disease, metabolic syndrome and dyslipidemia. Although these
associations may largely involve the ability of LPS to induce systemic inflammation, LPS
(and whole bacteria) in the circulation may also have direct effects on the vessel walls (e.g.,
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endothelial dysfunction) and atherosclerotic lesions (e.g., contribution to the formation of

fatty streaks and acceleration of plaque maturation and rupture). Moreover, endotoxemia
affects metabolism, as evidenced by a dyslipidemic lipoprotein phenotype; specifically,
endotoxemia is positively correlated with the concentration of triglycerides, cholesterol,
and apolipoprotein B and is negatively correlated with high-density lipoprotein cholesterol
concentration. Conversely, a high-fat diet can lead to increased levels of LPS in the
circulation; indeed, such diets have been associated with increased intestinal permeability
and metabolic endotoxemia. The authors conclude that metabolic endotoxemia may, in
part, explain why an unhealthy diet may increase the risk of not only cardiometabolic
disorders but also of other inflammatory diseases, including periodontitis. In other words,
endotoxemia may be regarded as a mechanistic link between periodontal disease and
cardiometabolic disorders.
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3. Periodontitis-atherosclerosis connection and dendritic cells

Dendritic cells (DC) contribute to host immune surveillance and link innate immune signals
to induction of T cell immunity. Key DC molecules involved in these interactions include
C-type lectins and other pattern-recognition receptors that facilitate antigen recognition
and uptake. Cutler and colleagues 42 review the basic biology and role of DCs in the
pathogenesis of periodontitis and systemic disease, such as atherosclerosis, and how this
cell type may contribute to the association of these comorbidities. The authors note that
work in humans and preclinical models has shown that myeloid DCs are readily mobilized
in both lymphoid and non-lymphoid tissues as well as in the bloodstream, in response
to oral microbial challenge. Intriguingly, however, the keystone periodontal pathogen P.
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gingivalis can invade DCs in the periodontal tissue or in the peripheral blood by means of a
distinct fimbrial adhesin that interacts with the C‑type lectin DC‑specific ICAM3-grabbing
non-integrin (DC‑SIGN). As DCs are highly migratory cells, the ability of P. gingivalis to
invade and survive within DCs may lead to the systemic dissemination of this pathogen
including to atherosclerotic plaques. This notion is consistent with clinical observations that
periodontitis-associated bacteremias elevate the P. gingivalis content of myeloid DCs in the
blood as well as the frequency of the carrier myeloid DCs. Consistently, P. gingivalis has
been immuno-colocalized with DCs in atheromatous plaques of patients with periodontitis

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patients. The microbial cargo of P. gingivalis-carrying myeloid DCs in the blood contains
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additional oral and non-oral species that may also contribute to systemic inflammation, in
part by contributing to pathologic reprogramming of DCs, rendering them pro-inflammatory
and pro-atherogenic. The authors suggest that tailored DC-derived exosomes (derived
from tolerogenic DCs, i.e., enriched in anti-inflammatory molecules) may be a novel
immunotherapeutic strategy to prevent or mitigate DC-mediated inflammatory responses,
thereby promoting oral and systemic health.

4. Pneumonia
Pneumonia is a prevalent infectious disease caused by a variety of microbial (bacterial,
viral, or fungal) pathogens that can infect the lungs. In a hospital setting, patients on
a ventilator may develop ‘ventilator-associated pneumonia’ if microbes in the breathing
tube get access to the patients’ lungs. Another type of hospital-associated pneumonia of
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emerging concern is non-ventilator hospital-acquired pneumonia (NV-HAP). Scannapieco

and colleagues 43 review recent evidence that NV-HAP is becoming a leading cause of
healthcare-associated infections despite being, at least in principle, a preventable infection.
The authors moreover discuss multiple studies that link poor oral health with increased risk
of NV-HAP. In this regard, the dental plaque biofilm is considered to be a reservoir for
respiratory infections, as oral microbes are commonly isolated from pneumonia patients,
most likely reaching the lungs via the oropharyngeal route. Consistent with this notion,
periodontitis is epidemiologically associated with increased risk of pneumonia, at least
in the elderly. Accumulating clinical evidence supports the importance of oral care as a
means to prevent NV-HAP. The authors recommend that the control of the oral biofilm
in susceptible populations can decrease the risk for NV-HAP by reducing the burden of
potential respiratory pathogens in the salivary secretions that can be potentially aspirated.
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5. Alzheimer’s disease
Clinical and microbial markers of periodontal disease have been associated with the
incidence and mortality of Alzheimer’s disease. According to the review of the relevant
literature by Eick and colleagues 44, this association might, at least in part, be causal
and two general mechanisms have been proposed: Direct effects of oral microorganisms
infiltrating the brain and the non-mutually exclusive mechanism that periodontitis may
aggravate Alzheimer’s disease pathology by increasing systemic inflammation. The authors
focus mainly on the first mechanism. Despite the overall evidence that suggests a connection
between oral microbial dysbiosis – which is exacerbated in old age – and Alzheimer’s
disease, the authors note inconsistencies among different studies. They propose the
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implementation of methodological consensus guidelines and the reporting of the storage

conditions of postmortem brain samples. They also review mechanistic insights derived from
animal and in vitro studies on microorganisms in the context of Alzheimer’s disease. Based
on both human and animal model-based studies, it seems that a number of different oral
bacterial species might be associated with Alzheimer’s disease, despite a predominant focus
on P. gingivalis by most studies. The authors also discuss that the modification of the human
and mouse gut microbiome by probiotics promotes cognitive health. By the same rationale,
they argue, treatments that promote a symbiotic periodontal microbiota (periodontal therapy,

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probiotics, anti-inflammatory approaches, diets such as the Mediterranean) may also

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improve cognitive ability in the elderly, a notion that could be tested in future clinical trials.

6. Rheumatoid arthritis
Multiple clinical and epidemiological studies support a bidirectional association between
rheumatoid arthritis (RA) and periodontitis. Although RA and periodontitis have different
etiology (the former represents autoimmune and the latter dysbiotic inflammation), they
appear to share pathophysiological features and genetic risk factors. However, as Koziel
and Potempa show 45 in this volume, causal relationships may also link these two
inflammatory bone loss disorders. This notion is supported by observations that treatment
of RA exerts beneficial effects on the clinical outcome of periodontitis and, conversely,
treatment of periodontitis can mitigate disease activity in RA. The authors also discuss
mechanistic studies in mouse and rat models that are consistent with a causal relationship
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between periodontitis and RA. Indeed, pre-existing experimental periodontitis aggravates

subsequent experimental arthritis. Moreover, experimental arthritis aggravates periodontitis,
suggesting a bidirectional relationship between these two disorders. Furthermore, specific
periodontal bacteria can potentially contribute to the formation of altered host epitopes
and thus promote autoimmune reactions in rheumatoid arthritis-susceptible individuals.
Aggregatibacter actinomycetemcomitans induces host protein citrullination in neutrophils
by secreting the pore-forming toxin LtxA, which causes calcium influx and hyperactivation
of peptidyl-arginine deiminase (PAD) enzymes, as well as cytolysis, leading to the release
of the generated citrullinated autoantigens. P. gingivalis expresses a unique peptidyl-arginine
deiminase (PPAD), which can directly citrullinate proteins including host proteins. Thus,
both bacterial species may contribute to the generation of the anti-citrullinated protein
antibodies (ACPAs) that are rheumatoid arthritis-specific and can promote arthritis in
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individuals with HLA-DRB1 shared epitope alleles. Antigen mimicry, owing to structural
similarities between certain P. gingivalis proteins and host proteins, has also been postulated
as a candidate link between periodontitis and development of RA. In conclusion, the authors
have presented a strong case that the traditional viewpoint of the immunological processes
underlying the pathogenesis of RA is rather limited and needs to integrate the role of
bacteria as important environmental risk factors that can contribute to the autoimmune
inflammatory reactions in RA.

7. Osteoporosis
Yu and Wang 46 discuss the association of periodontitis with another inflammation-driven
bone loss disease, namely osteoporosis. Osteoporosis is an aging-associated bone disease
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hallmarking deterioration of bone mass, mineral density and architecture, thereby increasing
the risk of bone fracture. The authors’ analysis of the relevant literature (clinical studies
most of which involved postmenopausal women) indicate a correlation between systemic
low bone mineral density (BMD) and alveolar bone loss. Moreover, there is currently
modest evidence suggesting an association between systemic BMD and clinical attachment
loss in periodontitis. The periodontitis-osteoporosis connection is, in great part, attributed to
common risk factors, such as age-related systemic inflammation and oxidative stress, which
is a major cause of cellular senescence. These processes contribute to the uncoupling of

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bone resorption and bone formation, in other words disrupt the balance between osteoclasts
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and osteoblasts and cause net loss of bone. Vitamin D deficiency and smoking, two
other shared risk factors for periodontitis and osteoporosis, also promote net bone loss
by adversely affecting the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin
(OPG) ratio in both systemic and alveolar bone. Moreover, the complement system plays a
key role in the regulation of the overall host inflammatory response and studies in relevant
preclinical models showed that complement C3 activation is required for the induction
of both periodontal and osteoporotic bone loss. Thus, individuals in whom complement
is dysregulated might be predisposed to increased susceptibility to both periodontitis
and osteoporosis. The authors conclude that a better understanding of the factors and
mechanisms underlying the connection of periodontitis and osteoporosis may lead to an
interdisciplinary management of both bone loss disorders through the use of common
therapeutics.
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8. Chronic kidney disease

The prevalence of severe periodontitis is significantly increased in patients with chronic
kidney disease (CKD). Although the two conditions share several risk factors, their
relationship might involve additional causes. Parsegian et al 47 comprehensively review
potential factors underlying this association, which include host, bacteriological, as well
as environmental factors. For instance, CKD-associated uremia leads to increased gingival
crevicular fluid levels of urea, thereby generating an alkaline pH environment that is
conducive for the growth of periodontal pathogens including P. gingivalis. CKD has also
been shown to dysregulate immune and inflammatory responses (e.g., impaired neutrophil
recruitment to tissues), which may aggravate microbiome-driven inflammatory conditions
such as periodontitis. CKD also exerts adverse effects on skeletal bone that may also affect
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the alveolar bone. Moreover, compared to non-renal controls, CKD patients have increased
abundance of periodontal disease-associated taxa and reduced abundance in certain health-
associated taxa. These dysbiotic changes might be the result of uremia, a notion that
is consistent with a preclinical model study showing that uremia-associated dysbiosis
contributes to increased periodontal bone loss. Specifically, transfer of oral microbiota
from uremic mice resulted in increased periodontal bone loss in germ-free recipient mice
than in germ-free mice receiving oral microbiota from healthy control mice. Interestingly,
some studies indicate that non-surgical periodontal therapy leading to improved clinical
periodontal parameters (clinical attachment loss and periodontal pocket depth) may also
improve renal parameters (e.g., glomerular filtration rate). However, stronger evidence from
randomized controlled trials is required before concluding that periodontitis affects CKD
and that periodontal treatment can improve renal disease parameters. In this regard, the
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authors discuss the limitations regarding the interpretation of current periodontitis-CKD

association studies and the effects of non-surgical periodontal therapy on the renal status
of CKD patients. Parsegian et al also make recommendations on how future studies can
be designed in a manner that can yield enhanced insight into the nature of the association
between periodontitis and CKD. The authors conclude that, although periodontitis and CKD
are complex conditions with common behavioral, social, and other confounding factors, the

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two conditions may also be independently connected, a notion that can be strengthened by
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future studies.

9. Chronic liver disease

Under certain conditions, oral pathogens may translocate and colonize the gastrointestinal
tract where they may aggravate dysbiosis and inflammation. These ectopically colonized
oral pathogens may also disseminate to the liver where they can exacerbate liver disease.
Albuquerque-Souza and Sahingur 48 review this oral–gut–liver microbial and immune axis
and its medical implications. If this axis is adequately understood, it could lead to novel
insights into the pathogenesis of periodontitis and comorbid diseases, such as chronic liver
disease including non-alcoholic fatty liver disease (NAFLD), which is a major focus of
these authors’ review. NAFLD is a condition involving excessive fat accumulation (steatosis)
in the liver in the absence of significant consumption of alcohol, and may be associated
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with obesity and metabolic syndrome. NAFLD may progress to nonalcoholic steatohepatitis
(NASH), in which fat accumulation together with liver inflammation may result in fibrosis
and eventually cirrhosis (advanced scarring/fibrosis), which may be accompanied by
hepatocellular carcinoma. Recent epidemiological studies have suggested an association
between periodontitis and NAFLD. Although these two diseases share numerous risk
factors, a causal link is possible although not yet proven. In support of a direct association
between periodontitis and chronic liver disease, periodontal treatment appears to change
the composition of the gut microbiota of cirrhotic patients and to modulate their systemic
immune response. Albuquerque-Souza and Sahingur also discuss potential mechanisms
whereby periodontal pathogens may affect liver pathophysiology. The authors conclude
that whereas available evidence (mostly based on preclinical models) supports a possible
link between NAFLD and periodontitis, future studies are warranted to strengthen the
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association, determine if the association is bidirectional, and dissect further the biological
mechanisms that link periodontitis and NAFLD.

10. Intestinal inflammation

Clinical observations together with studies in animal models have shown that the oral
cavity is a reservoir of resident microbial species that can ectopically colonize the gut
and contribute to or exacerbate intestinal pathologies. Although oral microbes cannot
readily colonize a healthy gut, they become enriched in the gut microbiota of patients
with inflammatory bowel disease, colon cancer, or liver cirrhosis. In general, factors that
trigger gut dysbiosis (e.g., inflammation, antibiotics and unhealthy diets) promote the
ability of oral pathobionts to colonize the gut. Kitamoto and Kamada 49 review recent
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mechanistic insights into the connection of periodontitis with intestinal inflammation from
both a microbiological and an immunological viewpoint. Swallowed oral pathobionts can
reach the gut through the oro-digestive tract and can promote colitis in susceptible hosts,
in part, by interacting with local inflammatory macrophages that are thereby induced
to secrete proinflammatory cytokines. Translocated oral pathobionts can also exacerbate
gut inflammation by promoting gut dysbiosis and impairing intestinal barrier function.
Intriguingly, moreover, pathogenic IL-17-secreting CD4+ T cells, which are primed in the
oral cavity (e.g., as a result of periodontal disease), can transmigrate through the lymphatic

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circulation to the gut, where they are reactivated by ectopic oral pathobionts (upon their
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processing by antigen-presenting cells). In this manner, transmigrated T cells of oral

origin can aggravate colitic inflammation. The authors conclude that the recent mechanistic
insights into the pathological oral-gut axis can offer new therapeutic options for treating
related comorbidities and discuss several potential approaches.

11. Cancer
Two reviews deal with the association of different forms of cancer with specific periodontal
pathogens, the first one involving P. gingivalis and the other with F. nucleatum.

11.1. Porphyromonas gingivalis and orodigestive squamous cell carcinoma

In contrast to the long-established potential of viruses as carcinogenic agents, interest in
the role of bacteria in the etiology of cancer is relatively recent, having gained momentum
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after the association of Helicobacter pylori with gastric cancer in the 1990s. Lamont and
colleagues 50 review emerging evidence for an association between periodontal pathogens,
such as P. gingivalis, and oral/orodigestive squamous cell carcinoma. Although the
discussed studies are correlative and causality remains to be addressed, the authors describe
potential carcinogenic mechanisms, established in in vitro models, whereby P. gingivalis
may contribute to carcinogenesis. These include promotion of host-cell proliferation and
resistance to apoptosis, reduced susceptibility of cancerous cells to chemotherapeutic agents,
generation of a dysbiotic inflammatory microenvironment conducive for tumor growth,
promotion of angiogenesis and metastasis. The carcinogenic potential of P. gingivalis is
furthermore supported by in vivo investigations in relevant animal models and is enhanced
in consortia with additional periodontal pathogens, such as Fusobacterium nucleatum. The
authors conclude that, whereas large longitudinal and intervention studies are required to
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establish a causative role for P. gingivalis (and other pathogens) in oral cancer, the current
knowledge may pave the way to the discovery of novel targets for early diagnosis.

11.2. Fusobacterium nucleatum role in colorectal and breast cancer

Metagenomic-epidemiological studies and experimental evidence from animal models have
linked F. nucleatum with the progression of certain tumor types, including colorectal cancer
(CRC) and breast cancer. Bachrach and colleagues 51 initially review the mechanism
underlying tumor-specific colonization (tumor tropism) by F. nucleatum, which appears
to translocate to colorectal tumors via the hematogenous route, although the contribution
of the orodigestive route cannot be formally ruled out. The tropism of F. nucleatum for
CRC cells is dependent on its Fap2 lectin, which has affinity for a carbohydrate moiety
(Gal-GalNAc) that is overexpressed in CRC as well as in different adenocarcinomas, e.g.,
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of the esophagus, pancreas, prostate, ovary, and breast. Evidence that F. nucleatum is
enriched in the breast cancer microbiome further supports the notion that this organism can
access tumors via the hematogenous route. Moreover, the authors examine the mechanisms
whereby this oral pathobiont contributes to tumor exacerbation. Specifically, they discuss
the ability of F. nucleatum to (i) enhance tumor cell proliferation and metastasis; (ii)
induce a tumor-permissive immune microenvironment; (iii) inhibit the recruitment of tumor-
infiltrating lymphocytes; (iv) promote chemoresistance (at least in CRC); and (v) activate

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immune checkpoints, thereby suppressing the anti-tumor activity of T cells and natural killer
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cells. The latter mechanism also involves the participation of the Fap2 lectin which activates
the inhibitory immunoreceptor TIGIT (T cell immunoreceptor with immunoglobulin and
ITIM domains). The authors conclude that the elucidation of the mechanisms that mediate
fusobacterial tumor tropism and tumor progression may facilitate innovative approaches
for treating tumors associated with this oral pathobiont. Moreover, on the basis of the
overabundance of F. nucleatum in certain tumors, the authors support the notion that this oral
pathobiont is a potential diagnostic biomarker at least for CRC.

12. Adverse Pregnancy outcomes

Multiple epidemiological studies indicate an association between periodontitis and adverse
pregnancy outcomes, such as preterm birth, low birthweight, miscarriage, preeclampsia,
intrauterine growth retardation, neonatal sepsis, and stillbirth. Xu and Han 52 review and
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discuss the epidemiological evidence as well as mechanistic and interventional/therapeutic

studies that could suggest a causal relationship between periodontitis and pregnancy
complications. The authors cite a recent case-control study that showed that the prevalence
of preterm delivery increased with increasing severity of gingivitis or periodontitis, thus
enhancing the plausibility of causality. A cause-and-effect relationship is supported by
studies in preclinical models, most of which involved investigation of the effects of
F. nucleatum in pregnant mice. Two major mechanisms have been proposed: (i) Direct
effects of disseminated oral microorganisms (or their products) in the fetal-placenta unit
and (ii) periodontitis-associated systemic inflammation affecting the fetal-placenta unit.
With regard to the first mechanism, several oral bacteria, including Bergeyella spp., F.
nucleatum, P. gingivalis and A. actinomycetemcomitans, were identified in the amniotic
fluid, cord blood and/or placenta in cases with preterm birth, preeclampsia, neonatal
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sepsis or stillbirth. Regarding the second and non-mutually exclusive mechanism, patients
with severe periodontitis have elevated concentrations of pro-inflammatory molecules
(e.g., IL-1, IL-6, C-reactive protein and fibrinogen) in the blood; these can presumably
stimulate the production in the fetal-placenta unit of inflammatory mediators, such as
prostaglandins, thereby causing intrauterine inflammation. However, interventional studies
aimed to determine whether periodontal treatment during pregnancy can mitigate the risk
for adverse pregnancy outcomes have yielded inconsistent results. Studies in preclinical
models have suggested that maternal supplementation of omega-3 fatty acids may protect
the fetuses by restraining inflammation; this approach might also be effective in human
periodontitis-associated pregnancy complications, given the results of clinical trials that the
adjunctive use of omega-3 fatty acids reduces clinical attachment loss and probing depth.
The authors conclude that, whereas epidemiological studies unequivocally indicate that
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periodontal disease is positively correlated with adverse pregnancy outcomes, further studies
are warranted to: i) dissect the precise molecular mechanisms involved; and ii) to design
more appropriate intervention trials to test for a causality between periodontitis and adverse
pregnancy outcomes, ultimately leading to treatments that promote oral health and reduce
the risk of pregnancy complications.

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13. Viruses and the oral cavity

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Two reviews deal with the potential role of viruses in periodontitis and associated
comorbidities, focusing predominantly on herpesviruses and the novel coronavirus, SARS-
CoV-2, the cause of COVID-19.

13.1. Viruses, periodontitis, and comorbidities

Besides bacteria, the oral mucosal tissues harbor also other microorganisms, including
archaea, fungi, and viruses; however, the connection of periodontitis with systemic disease
is predominantly studied in the context of the bacteriome. Teles and colleagues 53 review
the literature and explore the biologically plausible hypothesis that viruses may have an
analogous role in the connection between periodontal diseases and systemic comorbidities.
First, they discuss the connection of viruses with periodontitis. Although a number of
studies have shown a correlation between oral viral infection (e.g., herpes herpesviruses)
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and periodontitis, it is uncertain whether this association is causal (viruses directly

contributing to periodontal disease pathogenesis) or consequential, i.e., viral replication and
thus detection results from the ability of certain inflammatory mediators to support viral
replication. In either case, however, an active viral infection may exacerbate periodontitis
through several plausible mechanisms: Viruses may potentially promote the pathogenicity of
bacteria, may have direct cytopathic effects on stromal cells of the periodontium, and can
also either enhance inflammation or suppress immune responses, both of which can disrupt
periodontal tissue homeostasis. The authors suggest that longitudinal and interventional
clinical studies are warranted to conclusively determine whether viruses indeed contribute
to the pathogenesis of periodontitis. Viruses of the oral mucosal tissues may, at least in
principle, contribute to diseases in extra-oral sites. In this regard, the oral cavity is a site
of transmission of viruses, either through the saliva (e.g., transmission of Epstein–Barr
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virus, cytomegalovirus, and herpes simplex virus) or through the blood circulation, where
viruses can gain access and contribute to systemic disorders. In this context, viruses found in
periodontitis, such as cytomegalovirus, herpes simplex virus, type-2, and Epstein-Barr virus,
have been associated with cardiovascular disease and pre-eclampsia. The periodontium
may also be a reservoir for two recently described viruses, the novel coronavirus SARS-
CoV-2 and the small circular DNA virus redondovirus. Observations that the oral cavity
is a site of SARS-CoV-2 infection and likely a reservoir and site of transmission for
the virus, even more so in the presence of periodontitis, might in part explain the
recent association of periodontitis with COVID-19. The newly established association of
redondovirus sequences with both periodontitis and critical respiratory illness (increased
levels levels of redondoviruses in oropharyngeal samples of critically ill patients and in the
lungs of intubated patients), suggests that this virus might be implicated in oropharyngeal
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aspiration pneumonia. The authors conclude that open-ended approaches (metagenomics

and metatranscriptomics) can be used to better study the relationship of viruses within the
overall microbiome (bacterial, viral and fungal communities). The ultimate goal would be
to develop strategies for diagnosis and treatment of systemic diseases in which periodontal
viruses play a contributing role.

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13.2. COVID-19
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The coronavirus disease 2019 (COVID-19), a viral pandemic infection caused by

severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with
an overexuberant inflammatory response and can potentially affect multiple organs in
susceptible individuals. COVID-19 and periodontitis share several risk factors, such as,
diabetes, hypertension, and obesity among others. However, even after adjusting for
potential confounders, periodontitis still appears to be associated with COVID-19; in
particular, a recent case-control study of 568 participants showed that periodontitis is
significantly associated with increased risk of intensive care unit admission, necessity of
assisted ventilation, and death of patients with COVID-19. Tamimi and colleagues 54 discuss
this study and review possible factors that may explain the association of periodontal disease
and COVID-19. Among factors that could, at least in principle, predispose to increased
susceptibility to COVID-19 are alterations in the inflammatory responsiveness of patients
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with periodontitis. In other words, a chronic inflammatory condition, such as periodontitis,

could aggravate the course of COVID-19. In this regard, periodontitis is associated with
systemic inflammation and immunometabolic alterations (in systemic tissues including
the bone marrow), which in turn could prime the immune system to an exaggerated
inflammatory response following COVID-19 infection in susceptible patients. Clinical
observations also indicate that the oral cavity may be an important site for SARS-CoV-2
infection. If the oral mucosa, including the periodontal pockets, is a reservoir of SARS-
CoV-2, this could provide partial explanation for the periodontitis-COVID-19 connection.
Additional future studies are warranted to confirm and strengthen the currently limited
evidence for a direct periodontitis–COVID-19 connection. More research is also required to
dissect the exact mechanisms underlying this association. From a medical and therapeutic
viewpoint, it is important to discover whether the link between periodontitis and COVID-19
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is simply a correlative one or due to causal mechanisms that can be controlled, thus helping
reduce the risk of COVID-19 complications.

14. Bone marrow and periodontitis-associated comorbidities

Oral health is reciprocally related to systemic health and, not surprisingly, a bidirectional
relationship often exists between periodontitis and linked comorbidities. Periodontitis and
other chronic inflammatory diseases are moreover associated with aging-related elevation
of systemic inflammation, known as ‘inflamm-aging’, and their severity and prevalence
increases with advanced age. However, little has been achieved in our understanding
of reciprocal causal relationships between periodontitis and comorbidities and why the
susceptibility to these disorders increases with aging. Hajishengallis and colleagues 55
review the literature on two recently emerged concepts, trained innate immunity (TII)
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and clonal hematopoiesis of indeterminate potential (CHIP) that could offer novel insights
into these questions. Given that chronic diseases are largely driven by the action of
inflammatory immune cells, pro-proliferative and pro-inflammatory alterations to their
precursors in the bone marrow, i.e., the hematopoietic stem and progenitor cells (HSPCs),
may affect multiple disorders that emerge as comorbidities. Alterations to HSPCs that
can give rise to myeloid progeny cells with increased inflammatory capacity may result
from two non-mutually exclusive phenomena; (i) TII, an epigenetically based memory state

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 Hajishengallis Page 12

of enhanced immune responsiveness to future challenges and (ii) CHIP, the age-related
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acquisition of somatic mutations that confer clonal expansion advantage to affected HSPCs
and heightened inflammatory activity to their mutant myeloid progeny. The authors review
the relevant literature which suggests that (i) maladaptive TII may causally link periodontitis
and comorbidities, whereas CHIP, the prevalence of which increases with aging, can
aggravate the severity of these disorders. However, more evidence is required to establish the
underlying inflammatory axis between the bone marrow and peripheral tissue inflammation.
Such mechanistic insights into the comorbid connection of periodontitis and systemic
diseases may pave the way to novel diagnostic and therapeutic targets for their holistic
treatment.

15. Conclusion and outlook

The epidemiological, clinical interventional and animal model-based studies discussed in the
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various chapters of this volume collectively indicate that the association of periodontitis
and linked comorbidities is quite complex, involving both common risk factors and
pathophysiology as well as bidirectional causal relationships (independent of known
confounding factors). Despite the enormous progress made in the field 17,34,35,56–63,
unequivocal evidence that effective treatment of periodontitis can ameliorate the risk or
incidence of epidemiologically-lined comorbidities conditions is not currently available.
In this regard, multi-center randomized controlled clinical trials are required to implicate
periodontitis as a modifiable risk factor for linked comorbidities. Further improvement of
local periodontal treatment via innovative adjunctive host-modulation approaches 39,40, such
as by modulating complement with the C3-targeted drug AMY-101, which showed efficacy
in a recent phase 2a trial in patients with periodontal inflammation 37,38, may greatly
contribute to prevent systemic inflammation and promote overall health.
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Achieving a holistic and mechanistic understanding of periodontitis-associated

comorbidities may lead to new therapeutic options for the treatment of periodontitis and
associated comorbidities. Some of these novel approaches may be ‘central’ rather than
‘local’, for instance the targeting of maladaptive training of hematopoietic progenitors in
the bone marrow as a central hub linking distinct comorbidities. It is therefore important
to accelerate the transfer of research findings from basic and clinical studies into routine
clinical practice.

Acknowledgements
The author’s research is supported by grants from the U.S. National Institutes of Health (DE024153, DE029436,
DE026152, DE028561 and DE031206). The figure was created using Biorender.com.
Author Manuscript

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Figure 1: Periodontitis and comorbidities.

The indicated periodontitis-associated disorders are reviewed in this volume.
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Figure 2: Potential mechanisms connecting periodontitis to systemic inflammation.

For details on the indicated mechanisms (1-4) see text and relevant reviews in this volume.
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